Benzamide compounds are used as intermediates for the synthesis of many pharmaceutical therapeutic drugs. In particular, 2-amino-4,6-dimethoxybenzamide was reported as an intermediate in U.S. Pat. No. 3,966,965 for the synthesis of oxamic acid derivatives for prevention of hypersensitivity in allergic reactions. More recent patents describe this compound as a valuable intermediate en route to new cardiovascular agents (U.S. 2008/0188467 and WO2008/92231 to Resverlogix Corp.).
2-Amino-4,6-dimethoxybenzamide has been prepared from 4,6-dimethoxyisatoic anhydride. The 4,6-dimethoxyisatoic anhydride was, in turn, prepared by a reaction of 4,6-dimethoxyanthranilic acid with phosgene (U.S. Pat. No. 4,191,840 and Org. Synth. 1947, 27, 45). A different route converts 3,5-dimethoxyaniline to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin. The isatin is converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCI/HOBt-mediated coupling to produce 2-amino-4,6-dimethoxybenzamide (WO 2008/92231).
The known processes for the synthesis of benzamide compounds and its derivatives often involve unstable intermediates, inefficient processes, and in some cases, a large number of steps, which result in yields that are unacceptably low, and manufacturing costs that are unacceptably high, for commercial use. There is a need in the art for commercially feasible processes for making benzamide compounds and their derivatives.